10-69295633-G-T

Position:

• chr10-69295633-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001358263.1(HK1):​c.28G>T​(p.Ala10Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,606,244 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: HK1 NM_001358263.1 missense, splice_region
• Scores: Splicing: ADA: 0.1046
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.765

Genes affected

HK1 (HGNC:4922): (hexokinase 1) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HK1. . Trascript score misZ 5.1108 (greater than threshold 3.09). GenCC has associacion of gene with retinitis pigmentosa 79, non-spherocytic hemolytic anemia due to hexokinase deficiency, neurodevelopmental disorder with visual defects and brain anomalies, Charcot-Marie-Tooth disease type 4G.
• BP4: Computational evidence support a benign effect (MetaRNN=0.003704846).
• BP6: Variant 10-69295633-G-T is Benign according to our data. Variant chr10-69295633-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2428596.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-69295633-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000742 (113/152308) while in subpopulation SAS AF= 0.0214 (103/4824). AF 95% confidence interval is 0.018. There are 1 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HK1	NM_001358263.1	c.28G>T	p.Ala10Ser	missense_variant, splice_region_variant	4/21	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.28G>T	p.Ala10Ser	missense_variant, splice_region_variant	4/21		NM_001358263.1	ENSP00000494664

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00264 AC: 664 AN: 251398 Hom.: 14 AF XY: 0.00339 AC XY: 460 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0207

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00131 AC: 1909 AN: 1453936 Hom.: 36 Cov.: 28 AF XY: 0.00186 AC XY: 1344 AN XY: 723912

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0198

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 05, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.15
DANN	Benign	0.56
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	.;T;T;T;T;.
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Uncertain	-0.082	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	.;N;.;.;.;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;D;.;.;.;.
Sift4G	Benign	0.55	.;T;T;.;.;.
Polyphen		0.0	B;.;B;.;.;B
Vest4		0.11
MVP		0.33
ClinPred		0.027	T
GERP RS		-3.8
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201626997; hg19: chr10-71055389;